PROJECT SUMMARY Episodic memory decline is a hallmark feature of Alzheimer's Disease. Yet notable declines in memory are also prevalent in the majority of our aging population, which does not meet criteria for dementia. Understanding how memory dysfunction in these non-demented, healthy older adults differs from individuals with (or at risk for) dementia will require further investigation of the neurobiological substrates that contribute to memory in aging, which is the focus of this proposal. Here, we aim to characterize age-related differences in hippocampal white and gray matter microstructure using high-resolution, multi-compartment diffusion imaging. Traditional, single-compartment diffusion imaging studies have predominantly revealed age-related decreases in white matter microstructure, with large age effects in tracts that project to the hippocampus (fornix, perforant path). It remains unclear, however, whether this selective vulnerability of hippocampal white matter to aging can be attributed to distinct neurobiological substrates (axonal degeneration, demyelination). Moreover, single- compartment diffusion imaging is not commonly used to study gray matter because it is not sensitive to neurite (axon, dendrite) structure within this tissue. However, gray matter in the hippocampus exhibits highly organized neurite structure that is suitable for interrogation with multi-compartment diffusion imaging. Relative to single- compartment approaches, multi-compartment diffusion imaging provides more accurate indices of neurite microstructure. Using a high-resolution version of this novel imaging approach, we propose to test whether age differences in hippocampal white (Specific Aim 1) and gray (Specific Aim 1) matter can be attributed to distinct neurobiological substrates that vary by tissue type (axonal degeneration, dendritic de-arborization). We further aim to test whether these more accurate markers of hippocampal aging account for age-related declines in mnemonic processes that rely on the hippocampus (Specific Aim 3). Taken together, this proposal is an important step toward our long-term goal of clarifying the neural substrates being measured using human diffusion imaging by directly relating in vivo and ex vivo assessments of these substrates within the same aged individuals. The proposed study also has the potential to identify a neuroimaging marker that dissociates memory dysfunction in healthy aging versus dementia.